Lipid based drug delivery systems are well known in the art of pharmaceutical science. Typically they are used to formulate drugs having poor bioavailability or high toxicity or both. Among the prevalent dosage forms that have gained acceptance are many different types of liposomes, including small unilamellar vesicles, multilamellar vesicles and many other types of liposomes; different types of emulsions, including water in oil emulsions, oil in water emulsions, water-in-oil-in-water double emulsions, submicron emulsions, microemulsions; micelles and many other hydrophobic drug carriers. These types of lipid based delivery systems can be highly specialized to permit targeted drug delivery or decreased toxicity or increased metabolic stability and the like. Extended release in the range of days, weeks and more are not profiles commonly associated with lipid based drug delivery systems in vivo.
Ideally sustained release drug delivery systems should exhibit kinetic and other characteristics readily controlled by the types and ratios of the specific excipients used. Advantageously the sustained release drug delivery systems should provide solutions for hydrophilic, amphipathic as well as hydrophobic drugs.
Periodontitis
The use of systemic doxycycline and NSAIDs in combination therapy has been shown to suppress tissue damage in the gingiva of chronic periodontitis patients. Tissue damage is caused by the action of pathogenic bacteria in combination with host matrix metalloproteinase (MMP) activity. Antibiotic treatment in combination with anti-inflammatory medication suppresses these two pathways. An increase in efficacy and reduction of side effects of treatment would be achieved by a means of releasing these medications locally in a controlled fashion.
Bone Augmentation
Bone diseases requiring bone augmentation include benign and malignant bone tumors, cancers situated in bones, infectious bone diseases, and other bone diseases of etiology related to endocrinology, autoimmunity, poor nutrition, genetic factors, and an imbalance between bone growth and resorption. Examples are diseases such as osteosarcoma/malignant fibrous histiocytoma of bone (PDQ), osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, fibrosarcoma and malignant fibrous histiocytoma, giant cell tumor of bone, chordoma, lymphoma, multiple myeloma, osteoarthritis, Paget's disease of bone, arthritis, degenerative changes, osteoporosis, osteogenesis imperfecta, bone spurs, renal osteodystrophy, hyperparathyroidism, osteomyelitis, enchondroma, osteochondroma, osteopetrosis, bone and joint problems associated with diabetes.
Immediate and delayed infection is a major complication in the field of orthopedics. Reducing the complications after orthopedic treatment will induce the efficiency and success of the orthopedic treatment and in some cases it will reduce the mortality. There is also a need to allow treatment in infected sites and to induce the efficacy of the treatment in the infected sites.
Another important aspect in the field of orthopedics or orthopedic surgery is the need to accelerate soft and hard tissue recovery in reparative and regenerative procedures.
Liposomes and Biodegradable Polymers in Drug Delivery
To date the use of lipids in conjunction with biopolymers has been contemplated but these have not yet been introduced successfully into clinical practice.
U.S. Pat. No. 3,773,919 to Boswell et al describes the use of polymers derived from alpha-hydroxycarboxylic acids, including lactic acid, glycolic acid, and copolymers thereof, and their use in sustained release formulations. Such polymer exhibit slow biodegradability but typically have limited drug-holding capacity.
Liposomes are described in U.S. Pat. No. 4,522,803 to Lenk et al. Liposomes typically exhibit adequate drug delivery drug-holding capacity but relatively limited in vivo half-lives. Many different types of liposomes have been developed for particular applications. Examples can be found in U.S. Pat. Nos. 5,043,166; 5,316,771; 5,919,480; 6,156,337; 6,162, 462; 6,787,132; 7,160,554, among others.
U.S. Pat. Nos. 6,333,021 and 6,403,057 to Schneider et al disclose microcapsules having a biodegradable membrane encapsulating a gas core. The membrane, comprising water insoluble lipids with up to 75% by weight of biodegradable polymers, encapsulating a core filled with air or a gas. The microcapsules may be non-coalescent, dry and instantly dispersible, and useful as delivery vehicles for therapeutically active agents and/or as contrast agents for imaging of body organs. The microcapsules are produced by a method in which a water-in-oil emulsion is made from an organic solution comprising a dissolved lipid and an aqueous solution containing a surfactant. The freeze-dried mixture is re-dispersed in an aqueous carrier, and the microcapsules are dried. The presence of water throughout the process precludes formation of a water-resistant, lipid-saturated matrix; thus, these materials are subject to bulk-type degradation in vivo.
U.S. Pat. Nos. 6,277,413 and 6,793,938 to Sankaram disclose biodegradable lipid/polymer-containing compositions, formed by the following process: a) forming a water-in-oil emulsion from a first aqueous phase and a volatile organic solvent phase comprising a volatile organic solvent, a biodegradable polymer or copolymer that is soluble in organic solvent, and a lipid; b) dispersing the “water-in-oil” emulsion into a surfactant-free second aqueous phase to form solvent spherules, and c) removing the volatile organic solvent from the solvent spherules to form a microsphere composition suspended in the second aqueous phase. The methods disclosed utilize aqueous solutions, precluding formation of a water-resistant, lipid-saturated matrix.
U.S. Pat. No. 4,882,167 to Jang discloses a controlled release matrix for tablets or implants of biologically active agents produced by dry direct compression of a hydrophobic carbohydrate polymer, e.g. ethyl cellulose; and a difficult-to-digest soluble component, i.e. a wax, e.g. carnauba wax, a fatty acid material, or a neutral lipid. The carbohydrate polymers utilized, are unsuitable for release on a scale of weeks or months following administration by injection or implantation. In addition, the compositions are produced without any solvents (aqueous or organic), precluding formation of the homogenous lipid-saturated matrix structures.
US patent application 2006/0189911 to Fukuhira et al discloses an anti-adhesion membrane of a honeycomb film made of polylactic acid as a biodegradable polymer and a phospholipid. No disclosure is provided for modification of the membrane for use as a delivery system, e.g. for antibiotics or NSAID drugs. In addition, the disclosed membranes are required to be cast under conditions of high humidity, thus precluding formation of a water-resistant, lipid-saturated matrix; these implants are accordingly subject to bulk-type degradation in vivo.
US patent application 2006/0073203 to Ljusberg-Wahren et al discloses an orally administrable composition comprising a dry mixture of polymer, lipid and bioactive agent, intended upon contact with water or gastrointestinal fluids to form particles comprising the lipid, the bioactive agent, and optionally also water. The polymers utilized, disintegrate in the digestive tract during the digestive process; e.g. a time period of less than one day. Such compositions are completely unsuitable for release on a scale of weeks or months following administration by injection or implantation.
None of the prior art provides compositions adapted to achieve sustained release or programmed release or controlled release from a lipid-saturated polymeric matrix for periodontal or orthopedic uses. None of the above references demonstrates use of the disclosed compositions in delivery of an NSAID compound, an antibiotic compound, or a compound useful for bone augmentation.